JP2813610B2 - Bile acid derivative, method for producing the same, and pharmaceutical composition containing the same - Google Patents
Bile acid derivative, method for producing the same, and pharmaceutical composition containing the sameInfo
- Publication number
- JP2813610B2 JP2813610B2 JP63262672A JP26267288A JP2813610B2 JP 2813610 B2 JP2813610 B2 JP 2813610B2 JP 63262672 A JP63262672 A JP 63262672A JP 26267288 A JP26267288 A JP 26267288A JP 2813610 B2 JP2813610 B2 JP 2813610B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- activity
- methyl
- group
- same
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
Abstract
Description
【発明の詳細な説明】 本発明は、胆汁酸誘導体、その製造方法およびそれを
含有する医薬組成物に関する。The present invention relates to a bile acid derivative, a method for producing the same, and a pharmaceutical composition containing the same.
本発明の誘導体は、次の一般式Ｉで表される。 The derivative of the present invention is represented by the following general formula I.
（式中、R1は水素原子またはヒドロキシル基を示し、
それぞれ６位と７位にあるメチル基とヒドロキシル基と
が、α配置かβ配置のいずれかであってもよい。） 換言すれば、化合物Ｉは、下記の天然の胆汁酸類の６
−メチル誘導体である。 (Wherein, R 1 represents a hydrogen atom or a hydroxyl group,
The methyl and hydroxyl groups at positions 6 and 7, respectively, may be in either the α or β configuration. In other words, compound I is a compound of the following natural bile acids:
-A methyl derivative.
すなわち、ウルソデスオキシコール酸（UDCA;3α,7β
にヒドロキシ基がある。）、ウルソコール酸（３α,7β
にヒドロキシ基がある;R1がヒドロキシ基である。）、
ケノデオキシコール酸（３α,7αにヒドロキシ基があ
る。）およびコール酸（３α,7αにヒドロキシ基があ
る;R1がヒドロキシ基である。） 本発明はまた、考えられ得るグリシン抱合態またはタ
ウリン抱合態のみならず、式Ｉの化合物の、生理学的に
許容し得る塩類に関する。That is, ursodesoxycholic acid (UDCA; 3α, 7β
Has a hydroxy group. ), Ursocholic acid (3α, 7β)
Has a hydroxy group; R 1 is a hydroxy group. ),
Chenodeoxycholic acid (having a hydroxy group at 3α, 7α) and cholic acid (having a hydroxy group at 3α, 7α; R 1 is a hydroxy group) The present invention also provides a possible glycine- or taurine-conjugated form. As well as the physiologically acceptable salts of the compounds of the formula I.
更に、化合物Ｉは、７位にあるヒドロキシ基のみなら
ず、６位にあるメチル基がα配置かまたはβ配置のいず
れかであってもよいから、本発明はまた、単一アイソマ
ー類または単一ジアステレオマー類およびそれらの混合
物に関する。In addition, the present invention also relates to single isomers or single isomers since compound I may have either the α- or β-configuration of the methyl group at the 6-position as well as the hydroxy group at the 7-position. It relates to one diastereomer and mixtures thereof.
上記の胆汁酸類は、抗消化不良剤（antidyspepti
c）、消化促進剤（eupeptic）、抗異脂肪症剤（antidys
lipidemic）および胆汁分泌促進剤（choleretic）とし
て胆石症の治療のために、人間医療上長期にわたって用
いられており、また一般に、胆汁の流れによる刺激並び
に胆汁の質的変化および／または量的変化を必要とする
すべての病状に長期にわたって用いられている。The bile acids mentioned above are used as antidyspeptic drugs (antidyspepti
c), digestive enhancer (eupeptic), antidyslipidemic (antidys
It has been used in human medicine for a long time in the treatment of cholelithiasis as a lipidemic) and as a choleretic agent (choleretic), and is commonly used to stimulate bile flow and qualitative and / or quantitative changes in bile. It has been used for a long time for all necessary medical conditions.
天然の胆汁酸類分子に治療に役立つ可能性があること
が、薬物動態的面、代謝的面または化学物理学的面（脂
肪親和性／水親和性の割合、安定性、臨界ミセル濃度）
に関して改善された医薬を得ようとする試みにおいて、
多数の合成または半合成の誘導体の開発を促進した。た
とえば、ヨーロッパ特許−Ａ−第83106708.7号、同−Ａ
−第84104598.2号、同−Ａ−第84109811.4号、同−Ａ−
第85115611.7号、および米国特許第4648995号、同第446
0509号、同第4545938号を参照されたい。Pharmacokinetic, metabolic or chemophysical aspects (lipophilic / water affinity ratio, stability, critical micelle concentration) that natural bile acid molecules may be therapeutically useful
In an attempt to obtain an improved drug with respect to
It has facilitated the development of a number of synthetic or semi-synthetic derivatives. For example, European Patent Nos. A-83106708.7,
No. 84104598.2, No.-A- No. 84109811.4, No.-A-
No. 85115611.7, and U.S. Pat.
Nos. 0509 and 4545938.
前記の米国特許は、特に７−メチル、７−ヒドロキシ
誘導体を開示している。これらの誘導体は、天然の胆汁
酸類の分子として比較すると、腸内菌相に対する抵抗力
が高いという利点があり、従って安定性が増大するのみ
ならず半減期も延長する。The aforementioned U.S. patents specifically disclose 7-methyl, 7-hydroxy derivatives. These derivatives have the advantage of being more resistant to the gut microbiota when compared to the molecules of natural bile acids, thus increasing not only the stability but also the half-life.
これらの利点およびその他の利点も、本発明の化合物
によってもたらされるものである。本発明の化合物は、
天然の胆汁酸類の分子と比較すると、６位にメチル基が
存在し、７位は事実上変化していないことを特徴として
いる。７位は薬理学的活性上重要であることが知られて
いるから、このこと自体は有利である。These and other advantages are provided by the compounds of the present invention. The compounds of the present invention
Compared to the molecule of natural bile acids, it is characterized by the presence of a methyl group at position 6 and the fact that position 7 is virtually unchanged. This is advantageous per se since position 7 is known to be important for pharmacological activity.
６位にあるメチル基は、この胆汁酸類の分子を一層親
性とし、また一層ミセルを形成しやすくする。このこと
は、たとえばUDCA自体に対するUDCA6−メチル誘導体の
場合と同様である。The methyl group at position 6 makes the molecule of bile acids more affinity and more likely to form micelles. This is, for example, the same as for the UDCA 6-methyl derivative for UDCA itself.
好気条件下、化合物Ｉを人糞とともにインキュベーシ
ョンすることにより、UDCAと比較したイン・ビトロ試験
を行なった。その結果、化合物ＩはUDCAより安定性が高
く、UDCAよりデオキシレーションが低いことおよび化合
物ＩとUDCAの半減期は、それぞれ24時間以上と８時間で
あることが判明した。An in vitro test compared to UDCA was performed by incubating Compound I with human feces under aerobic conditions. As a result, it was found that Compound I was more stable than UDCA, had lower deoxylation than UDCA, and the half-lives of Compound I and UDCA were 24 hours or more and 8 hours, respectively.
２μmol/分/kg体重の投与量で本発明の化合物をラッ
トに静脈内投与することにより行なった試験は、UDCAに
匹敵する胆汁分泌効果と胆汁中への本発明の化合物の効
率的な回収を立証した。この回収された化学生成物は、
UDCAの場合と同じ割合で、大部分がタウロー抱合態であ
り、一部がグリコー抱合態である。Studies performed by intravenously administering the compound of the present invention to rats at a dose of 2 μmol / min / kg body weight showed a bile secretion effect comparable to UDCA and an efficient recovery of the compound of the present invention in bile. Proven. This recovered chemical product is
At the same rate as in UDCA, most are tauro-conjugated and some are glycoconjugated.
脂質胆汁の分泌効果については、化合物Ｉは特異的に
コレステロールの分泌を減少させ、リン脂質の分泌を一
定に保つ。With respect to the secretion effect of lipid bile, Compound I specifically reduces cholesterol secretion and keeps phospholipid secretion constant.
本発明の化合物は、たとえば「Remington's Pharmace
utical Sciences Handbook（アメリカ合衆国、ニュー・
ヨーク市、Hack Pub.Co.出版）」の記載に従って、公知
の技術と公知の賦形剤により調製された医薬組成物の形
態で、企図された治療に使用するために投与される。The compound of the present invention can be used, for example, in “Remington's Pharmaceutical
utical Sciences Handbook (New, USA)
(Hack Pub. Co., York City), in the form of a pharmaceutical composition prepared by known techniques and known excipients for use in the intended treatment.
好ましい投与のルートは経口投与のルートであり、治
療すべき疾病と患者の状態によって変動する１日の投与
量は、原則として50〜500mgの範囲であり、１回または
２回以上に分けて投与する。The preferred route of administration is the oral route, and the daily dose which varies depending on the disease to be treated and the condition of the patient is, in principle, in the range of 50 to 500 mg, and is administered in one or more divided doses I do.
好適な医薬組成物の例は、カプセル剤、錠剤、糖衣丸
剤、糖衣ピル剤、シロップ剤、顆粒剤、液剤、バイアル
（vial）剤である。本発明の化合物はまた、外科手術の
前または後に、局所潅流することにより分散液または粉
末の形態で投与することもできる。Examples of suitable pharmaceutical compositions are capsules, tablets, sugar-coated pills, sugar-coated pills, syrups, granules, solutions, vials. The compounds of the present invention can also be administered in the form of a dispersion or powder by local perfusion, before or after surgery.
化合物Ｉの製造方法は、 一般式II （式中、R2はヒドロキシ保護基を示し、Ｒ′１は水素
原子またはヒドロキシが保護された基を示す。）で表わ
される化合物をコントロールされた条件下でメチル化す
ることからなる。The method for producing compound I is represented by general formula II Wherein R 2 represents a hydroxy-protecting group and R ′ 1 represents a hydrogen atom or a hydroxy-protected group under controlled conditions.
エノレート生成の際の速度論的制御を促進することが
できる適当な塩基溶媒とメチル ハライドとを用いてメ
チル化を行なう。Methylation is carried out using a methyl halide and a suitable base solvent capable of promoting kinetic control during the formation of the enolate.
ジエチルアミン、ジイソプロピルアミン、ピペリジ
ン、イソプロピルシクロヘキシルアミン、ヘキサメチレ
ンジシラジンなどのような二級アミンから誘導されるリ
チウム ジアルキルアミド類は、本発明における塩基と
して用いることができる。特に好ましいのは、リチウム
ジイソプロピルアミンかまたはイソプロピルシクロヘ
キシルアミンである。Lithium dialkylamides derived from secondary amines such as diethylamine, diisopropylamine, piperidine, isopropylcyclohexylamine, hexamethylenedisilazine and the like can be used as the base in the present invention. Particularly preferred is lithium diisopropylamine or isopropylcyclohexylamine.
好ましくは、ヘキサメチルホスホラミド（HMPA）の存
在下において好適な溶媒は、1,2−ジメトキシエタン、
テトラヒドロフラン、エチルエーテルである。Preferably, in the presence of hexamethylphosphoramide (HMPA), a suitable solvent is 1,2-dimethoxyethane,
Tetrahydrofuran and ethyl ether.
反応温度は、−50℃以下であり、好ましくは約−78℃
である。The reaction temperature is −50 ° C. or lower, preferably about −78 ° C.
It is.
その結果生成する化合物III を、脱保護基し、７位のケト基を還元して７−ヒドロキ
シル基にする。The resulting compound III Is deprotected and the keto group at the 7-position is reduced to a 7-hydroxyl group.
反応条件下で安定な基は、保護基として使用すること
ができる。特に好ましいのはテトラヒドロピラニル基で
ある。ケト基の還元は、従来使用されている反応によ
り、すなわち金属水素化物を用いるか、Meerwein−Ponn
dorf反応により、一番最後に行なうことができる。Groups which are stable under the reaction conditions can be used as protecting groups. Particularly preferred is a tetrahydropyranyl group. The reduction of the keto group is carried out according to the conventionally used reactions, i.e. using metal hydrides or Meerwein-Ponn
The last can be done by the dorf reaction.
未反応の化合物IIが混存しているために化合物IIIが
純粋でない場合には、メチルエステル混合物を用いてク
ロマトグラフィによる分離を行なうのが得策である。If compound III is not pure due to the presence of unreacted compound II, it is advisable to carry out chromatographic separation using a mixture of methyl esters.
次に実施例を挙げて本発明を更に詳細に説明する。本
発明はこの実施例によりなんら限定されるものではな
い。Next, the present invention will be described in more detail with reference to examples. The present invention is not limited by this embodiment.
実施例 ａ）３−α−テトラヒドロピラニロキシ ７−ケト−５
−β−コラン−24−オイック アシド（II） ３−α−ヒドロキシ−７−ケト−５−β−コラン−24
−オイック アシド（3.00g、7.68mmol）の無水ジオキ
サン（55ml）溶液に、パラートルエンスルホン酸（3.00
g、1.6mmol）を添加し、次いでこれに3,4−ジヒドロ−2
H−ピラン（DHP）（2.3g、27mmol）を徐々に添加した。
この反応混合物を室温で、15分間磁気撹拌し、次いでこ
れにpH8〜９のアンモニア飽和メタノールを添加した。
この混合物を真空下で蒸発させ、その残渣を取り出して
クロロホルムに溶解し、20mlの飽和NaHCO3溶液で２回洗
滌した。無水硫酸マグネシウム上で乾燥し、真空下で蒸
発させた後、その残渣（3.5g）をSiO2（φ４、14時間）
によりクロマトグラフィに付した。CHCl3/MeOH（95:5）
混合液を用いて溶出することによりジヒドロピランの重
合生成物を得た。次いでCHCl3/MeOH（90:10）混合液を
用いて、求める化合物Ｉ（2.7g）を得た。収率72％。Example a) 3-α-tetrahydropyraniloxy 7-keto-5
-Β-cholan-24-oic acid (II) 3-α-hydroxy-7-keto-5-β-cholan-24
Oic acid (3.00 g, 7.68 mmol) in anhydrous dioxane (55 ml) was added with para-toluenesulfonic acid (3.00 g, 3.00 g, 7.68 mmol).
g, 1.6 mmol), and then 3,4-dihydro-2
H-pyran (DHP) (2.3 g, 27 mmol) was added slowly.
The reaction mixture was magnetically stirred at room temperature for 15 minutes, then to this was added ammonia saturated methanol, pH 8-9.
The mixture was evaporated under vacuum, the residue was taken up and dissolved in chloroform and washed twice with 20 ml of a saturated NaHCO 3 solution. After drying over anhydrous magnesium sulfate and evaporating under vacuum, the residue (3.5 g) was extracted with SiO 2 (φ4, 14 hours)
For chromatography. CHCl 3 / MeOH (95: 5)
The polymerization product of dihydropyran was obtained by elution using the mixed solution. The desired compound I (2.7 g) was then obtained using a CHCl 3 / MeOH (90:10) mixture. Yield 72%.
Ｈ−NMR（CDCl3）δ:0.68（s,C−18 Me,3H）;0.9（d,
C−21 Me,3H）;1.17（s,C−19 Me,3H）;3.3−4.0（2m,C
−２′CH,C−６′CH2,3H）;4.6−4.8（brs,C−３ CH−
OH,1H） ｂ）３−α−テトラヒドロピラニロキシ−６−ξ−メチ
ル−７−ケト−５−β−コラン−24−オイック アシド
（III） ジイソプロピルアミン（1.41g、14mmol）のテトラヒ
ドロフラン（THF）（50ml）溶液にＮ−ブチル リチウ
ム（9.25ml、1.6Mヘキサン溶液）を添加し、次いでHMPA
（2.5g、14mmol）を添加した。この系を−78℃に冷却
し、酸II（2.00g、4mmol）のTHF（20ml）溶液を徐々に
添加した。添加終了後５分して、ヨウ化メチル（17.1
g、12mmol）を滴々添加した。次いでこの反応混合物を
室温に加温した後、これを10％HClで酸性とし、20mlの
クロロホルムで３回抽出した。この有機層を合わせて水
で洗滌し、硫酸ナトリウム上で乾燥し、真空下で蒸発さ
せた。この粗製化合物（2.00g）をSiO2（φ４、12時
間）を用いてクロマトグラフィに付した。CHCl3/MeOH
（98:2）混液で溶出することにより、出発化合物IIとメ
チル誘導体IIIの混合物を1.95g得た。 H-NMR (CDCl 3) δ : 0.68 (s, C-18 Me, 3H); 0.9 (d,
C-21 Me, 3H); 1.17 (s, C-19 Me, 3H); 3.3-4.0 (2 m, C
-2'CH, C-6'CH 2, 3H ); 4.6-4.8 (brs, C-3 CH-
OH, 1H) b) 3-α-tetrahydropyraniloxy-6-ξ-methyl-7-keto-5-β-cholane-24-oic acid (III) Tetrahydrofuran (THF) of diisopropylamine (1.41 g, 14 mmol) (50 ml) solution was added with N-butyllithium (9.25 ml, 1.6 M hexane solution) and then HMPA
(2.5 g, 14 mmol) was added. The system was cooled to -78 C and a solution of acid II (2.00 g, 4 mmol) in THF (20 ml) was added slowly. Five minutes after the end of the addition, methyl iodide (17.1)
g, 12 mmol) were added dropwise. The reaction mixture was then warmed to room temperature, after which it was acidified with 10% HCl and extracted three times with 20 ml of chloroform. The combined organic layers were washed with water, dried over sodium sulfate and evaporated under vacuum. The crude compound (2.00 g) was chromatographed on SiO 2 (φ4, 12 hours). CHCl 3 / MeOH
Elution with a (98: 2) mixture gave 1.95 g of a mixture of starting compound II and methyl derivative III.
ｃ）メチル３−α−ヒドロキシ−６−ξ−メチル−７−
ケト−５−β−コラノエートの分離 前項（ｂ）で得た化合物IIと化合物IIIの混合物（2.5
2g、5.12mmol）をTHF（4ml）に溶解し、これに数滴の37
％のHClを添加し、これを室温で30分間撹拌した。次い
で、これを25mlのクロロホルムで２回抽出した。この有
機層を合わせて無水硫酸ナトリウム上で乾燥し、減圧下
で蒸発させた。その結果、出発化合物と、保護基を脱離
した化合物IIIとからなる、2gの混合物を得た。この混
合物をメタノール（200ml）に溶解し、その生成した溶
液にパラ−トルエンスルホン酸（0.400g）を添加した。
これを室温で12時間、ゆっくりと磁気撹拌した後、真空
下で溶剤を蒸発させた。その残渣を取り出してクロロホ
ルムに溶解し、これを20mlの水で２回洗滌した。この有
機層を無水硫酸ナトリウム上で乾燥し、得られた粗製化
合物を、SiO2（φ５、20時間）を用いてフラッシュ ク
ロマトグラフィーに付した。クロロホルムを用いて溶出
することにより、1.00gの標記化合物を得た。収率50％ Ｈ−NMR（CDCl3）δ:0.68（s,C−18 Me,3H）;0.9（d,
C−21 Me,3H）;1.17（s,C−19 Me,3H）;3.6（s,CO2CH3,
3H） また、0.98gの化合物VIを得た。c) Methyl 3-α-hydroxy-6-ξ-methyl-7-
Separation of keto-5-β-cholanoate A mixture of compound II and compound III obtained in (b) above (2.5
2g, 5.12mmol) in THF (4ml) and add a few drops of 37
% HCl was added and this was stirred at room temperature for 30 minutes. This was then extracted twice with 25 ml of chloroform. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. As a result, 2 g of a mixture consisting of the starting compound and the compound III from which the protecting group was eliminated was obtained. This mixture was dissolved in methanol (200 ml), and para-toluenesulfonic acid (0.400 g) was added to the resulting solution.
After slow magnetic stirring at room temperature for 12 hours, the solvent was evaporated under vacuum. The residue was taken out and dissolved in chloroform, which was washed twice with 20 ml of water. The organic layer was dried over anhydrous sodium sulfate, and the obtained crude compound was subjected to flash chromatography using SiO 2 (φ5, 20 hours). Elution with chloroform provided 1.00 g of the title compound. Yield 50% H-NMR (CDCl 3 ) δ: 0.68 (s, C-18 Me, 3H); 0.9 (d,
C-21 Me, 3H); 1.17 (s, C-19 Me, 3H); 3.6 (s, CO 2 CH 3 ,
3H) Further, 0.98 g of compound VI was obtained.
収率49％ ｄ）３−α−ヒドロキシ−６−ξ−メチル−７−ケト−
５−β−コラン−24−オイック アシド 前項（ｃ）で得たエステル（0.900g、2.1mmol）を10
％KOHメタノール溶液（20ml）中で３時間還流した。冷
却した後、この反応混合物を10％HClを用いて酸性に
し、15mlの酢酸エチルで３回抽出した。有機層を合わせ
て、これを10mlの水で２回洗滌し、無水硫酸ナトリウム
の上で乾燥して減圧下にこれを乾燥した。得られた残渣
をSiO2を用いてクロマトグラフィに付し、CHCl3/MeOH
（90:10）混液で溶出し、0.85gの標記の酸（純度98％）
を得た。Yield 49% d) 3-α-hydroxy-6-ξ-methyl-7-keto-
5-β-cholan-24-oic acid The ester (0.900 g, 2.1 mmol) obtained in (c) above was added to 10
The mixture was refluxed for 3 hours in a methanol solution of 20% KOH (20 ml). After cooling, the reaction mixture was acidified with 10% HCl and extracted three times with 15 ml of ethyl acetate. The combined organic layers were washed twice with 10 ml of water, dried over anhydrous sodium sulfate and dried under reduced pressure. The residue obtained is chromatographed on SiO 2 and CHCl 3 / MeOH
(90:10) eluted with the mixture, 0.85 g of the title acid (98% pure)
I got
m.p.95〜98℃； Ｈ−NMR（CDCl3）δ:0.68（s,C−18 Me,3H）;3.15〜
3.55（m,C−３ CH−OH,1H）;3.8〜4.0（brs,C−３ CH
−OH,1H） マス・スペクトル（50およびＶ）m/e404.2−386.7−2
92.9−230.0−216.1−117.4−83.7 ｅ）３−α−７−ξ−ジヒドロキシ−６−ξ−メチル−
５−β−コラン−24−オイック アシド 前項（ｄ）で得た化合物（0.460g、1.13mmol）を２級
ブタノール（15ml）に溶解した。その混液を還流し、金
属ナトリウム（0.460g）を添加した。mp95~98 ℃; H-NMR (CDCl 3) δ: 0.68 (s, C-18 Me, 3H); 3.15~
3.55 (m, C-3 CH-OH, 1H); 3.8 to 4.0 (brs, C-3 CH
−OH, 1H) Mass spectrum (50 and V) m / e 404.2−386.7−2
92.9-230.0-216.1-117.4-83.7 e) 3-α-7-ξ-dihydroxy-6-ξ-methyl-
5-β-cholane-24-oic acid The compound (0.460 g, 1.13 mmol) obtained in (d) above was dissolved in secondary butanol (15 ml). The mixture was refluxed and sodium metal (0.460 g) was added.
２時間後、その反応混合物を冷却し、5mlの水で稀釈
し、37％HClで酸性としてから10mlの酢酸エチルで３回
抽出した。After 2 hours, the reaction mixture was cooled, diluted with 5 ml of water, acidified with 37% HCl and extracted three times with 10 ml of ethyl acetate.
その有機フラクションを合わせて無水硫酸ナトリウム
上で乾燥し、減圧下で蒸発させた。得られた残渣をSiO2
（φ2.5、18時間）を用いてクロマトグラフィに付し、C
HCl3/MeOH（98:2）混液で溶出することにより、酸Ｉを
得た。The combined organic fractions were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The obtained residue is SiO 2
(Φ2.5, 18 hours)
Elution with a mixture of HCl 3 / MeOH (98: 2) provided acid I.
収率44％、m.p.128−132℃ Ｈ−NMR（CDCl3−CD3OD） δ:0.7（s,C−18 Me,3H）;1.00（t,C−19およびＣ−6
Me,6H）;3.45〜3.80（m,C−3CH−OH,1H）Yield 44%, mp 128-132 ° C H-NMR (CDCl 3 -CD 3 OD) δ: 0.7 (s, C-18 Me, 3H); 1.00 (t, C-19 and C-6)
Me, 6H); 3.45-3.80 (m, C-3CH-OH, 1H)
───────────────────────────────────────────────────── フロントページの続き (58)調査した分野(Int.Cl.6，ＤＢ名) C07J 9/00 ＣＡ（ＳＴＮ)──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int.Cl. 6 , DB name) C07J 9/00 CA (STN)
Claims (8)
れぞれ６位と７位にあるメチル基とヒドロキシル基と
が、α配置かβ配置のいずれかであってもよい。）で表
わされる化合物。1. A compound of the general formula I (Wherein, R 1 represents a hydrogen atom or a hydroxyl group, and the methyl group and the hydroxyl group at the 6-position and the 7-position, respectively, may be in either α-configuration or β-configuration). .
５−β−コラン−24−オイック アシド。(2) 3-α-7-dihydroxy-6-methyl-
5-β-cholan-24-oic acid.
−メチル−５−β−コラン−24−オイック アシド。(3) 3-α-7-12-α-trihydroxy-6
-Methyl-5- [beta] -cholan-24-oic acid.
子か保護されたヒドロキシ基を示す。）で表される化合
物を速度論的制御条件下でメチル化し、続いてその結果
生成した化合物を脱保護基して還元する、一般式Ｉの化
合物の製造方法。4. A compound of the general formula II: Wherein R 2 represents a hydroxy protecting group and R ′ 1 represents a hydrogen atom or a protected hydroxy group. The compound represented by the formula: A method for producing a compound of the general formula I, wherein the compound obtained is deprotected and reduced.
ンおよびエタノールからなる群から選んだ溶剤中におい
て、リチウム ジアルキルアミドの存在下にヨウ化メチ
ルを用いてメチル化を行う請求項４に記載の方法。5. The method according to claim 4, wherein the methylation is carried out using methyl iodide in the presence of lithium dialkylamide in a solvent selected from the group consisting of 1,2-dimethoxyethane, tetrahydrofuran and ethanol.
項のいずれかに記載の式Ｉの化合物。6. Claims 1-3 as therapeutic agents
A compound of formula I according to any of the clauses.
活性成分として含有する、抗消化不良（antidyspepti
c）活性、消化促進（eupeptic）活性、抗異脂肪症（ant
idyslipidemic）活性および胆汁分泌促進（chlolereti
c）活性を有する医薬組成物。7. An anti-digestive disease comprising the compound according to claim 1 as an active ingredient.
c) activity, eupeptic activity, anti-dyslipidemia (ant
idyslipidemic) activity and promotion of bile secretion (chlolereti)
c) An active pharmaceutical composition.
症活性および胆汁分泌促進活性を有する医薬の製造へ
の、請求項１〜３のいずれかに記載の化合物の使用方
法。8. Use of the compound according to any one of claims 1 to 3 for the manufacture of a medicament having anti-digestive activity, digestive promoting activity, anti-dyslipidemic activity and bile secretion promoting activity.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT22343A/87 | 1987-10-20 | ||
| IT22343/87A IT1223313B (en) | 1987-10-20 | 1987-10-20 | BILIARY ACID DERIVATIVES THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01135795A JPH01135795A (en) | 1989-05-29 |
| JP2813610B2 true JP2813610B2 (en) | 1998-10-22 |
Family
ID=11194953
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63262672A Expired - Fee Related JP2813610B2 (en) | 1987-10-20 | 1988-10-18 | Bile acid derivative, method for producing the same, and pharmaceutical composition containing the same |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US4921848A (en) |
| EP (1) | EP0312867B1 (en) |
| JP (1) | JP2813610B2 (en) |
| AT (1) | ATE75750T1 (en) |
| DE (2) | DE312867T1 (en) |
| ES (1) | ES2009723T3 (en) |
| GR (2) | GR890300125T1 (en) |
| IT (1) | IT1223313B (en) |
Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1229569B (en) * | 1989-04-17 | 1991-09-04 | Giuliani Spa | BILIARY ACID DERIVATIVES, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| US5650967A (en) * | 1995-07-06 | 1997-07-22 | Micron Technology, Inc. | Method and apparatus for writing and erasing flash memory |
| JP2002526193A (en) * | 1998-09-18 | 2002-08-20 | ユナイテッド ステイツ サージカル コーポレーション | Intravascular fastener applicator |
| USRE48286E1 (en) | 2001-03-12 | 2020-10-27 | Intercept Pharmaceuticals, Inc. | Steroids as agonists for FXR |
| ITMI20021532A1 (en) * | 2002-07-12 | 2004-01-12 | Roberto Pellicciari | CHEMICAL COMPOUNDS |
| US7319109B2 (en) | 2002-11-22 | 2008-01-15 | Smith Kline Beecham Corporation | Farnesoid X receptor agonists |
| EP1568706A1 (en) * | 2004-02-26 | 2005-08-31 | Intercept Pharmaceuticals, Inc. | Novel steroid agonist for FXR |
| DK1734970T3 (en) | 2004-03-12 | 2015-02-16 | Intercept Pharmaceuticals Inc | Treatment of fibrosis using FXR ligands |
| US10987362B2 (en) | 2004-03-12 | 2021-04-27 | Intercept Pharmaceuticals, Inc. | Treatment of fibrosis using FXR ligands |
| ITMI20050912A1 (en) * | 2005-05-19 | 2006-11-20 | Erregierre Spa | PROCESS OF PREPARATION OF ACIDS 3-A-YA (B) -DIDROSSI-6-A (B) -ALCHIL-5B-COLANICI |
| CN101679476B (en) * | 2007-01-19 | 2014-05-07 | 英特塞普特医药品公司 | 23-substituted bile acids as TGR5 modulators and methods of use thereof |
| BRPI0916735B8 (en) | 2008-07-30 | 2021-05-25 | Intercept Pharmaceuticals Inc | tgr5 modulating compounds, pharmaceutical compositions comprising them and their uses |
| MX2011005295A (en) | 2008-11-19 | 2011-06-24 | Intercept Pharmaceuticals Inc | Tgr5 modulators and method of use thereof. |
| US9982008B2 (en) | 2012-06-19 | 2018-05-29 | Intercept Pharmaceuticals, Inc. | Preparation and uses of obeticholic acid |
| CA3047776C (en) | 2012-06-19 | 2022-10-18 | Intercept Pharmaceuticals, Inc. | Preparation, uses and solid forms of obeticholic acid |
| EP3006557A1 (en) | 2014-10-07 | 2016-04-13 | Heinrich-Heine-Universität Düsseldorf | Bile acids for inducing hepatic differentiation |
| JP7021080B2 (en) | 2015-10-07 | 2022-02-16 | インターセプト ファーマシューティカルズ， インコーポレイテッド | Farnesoid X Receptor Modulator |
| CN106589039B (en) * | 2015-10-15 | 2019-12-17 | 苏州朗科生物技术股份有限公司 | preparation method of obeticholic acid and related compound |
| CN106939030A (en) * | 2017-04-07 | 2017-07-11 | 华东师范大学 | A kind of synthetic method of the keto lithcholic acid of intermediate 7 of shellfish cholic acid difficult to understand |
| CN107021994B (en) * | 2017-04-07 | 2020-12-22 | 华东师范大学 | Synthetic method of intermediate 3 alpha-hydroxy-7-ketone-5 beta-cholestane-24-acid of obeticholic acid |
| CN106995478A (en) * | 2017-04-07 | 2017-08-01 | 华东师范大学 | A kind of synthetic method of the keto lithcholic acid of intermediate 7 of urso |
| CN107033208A (en) * | 2017-04-07 | 2017-08-11 | 华东师范大学 | A kind of synthetic method of 7 keto lithcholic acid |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2615902A (en) * | 1950-10-24 | 1952-10-28 | Merck & Co Inc | Chemical compounds and processes for preparing the same |
| US2966499A (en) * | 1958-04-09 | 1960-12-27 | Merck & Co Inc | Oxidation of cholic acid with chlorine |
| US2938031A (en) * | 1958-12-11 | 1960-05-24 | Searle & Co | 17-carboxyalkylated 3-oxygenated 6-methylandrosten-17-ol lactones and intermediates |
| US3591687A (en) * | 1968-03-13 | 1971-07-06 | George A Bray | Bile acids and derivatives thereof as anorectic agents |
| US4172076A (en) * | 1977-04-04 | 1979-10-23 | Diamond Shamrock Corporation | Process for preparing steroidal acids and their intermediate derivatives |
| US4460509A (en) | 1981-08-19 | 1984-07-17 | Beth Israel Medical Center | Chemical synthesis |
| US4648995A (en) | 1983-11-02 | 1987-03-10 | Beth Israel Medical Center | Chemical synthesis |
| US4545938A (en) | 1983-11-02 | 1985-10-08 | Beth Israel Medical Center | Chemical synthesis |
-
1987
- 1987-10-20 IT IT22343/87A patent/IT1223313B/en active
-
1988
- 1988-10-10 ES ES198888116747T patent/ES2009723T3/en not_active Expired - Lifetime
- 1988-10-10 DE DE198888116747T patent/DE312867T1/en active Pending
- 1988-10-10 EP EP88116747A patent/EP0312867B1/en not_active Expired - Lifetime
- 1988-10-10 DE DE8888116747T patent/DE3870801D1/en not_active Expired - Fee Related
- 1988-10-10 AT AT88116747T patent/ATE75750T1/en not_active IP Right Cessation
- 1988-10-18 JP JP63262672A patent/JP2813610B2/en not_active Expired - Fee Related
- 1988-10-19 US US07/259,870 patent/US4921848A/en not_active Expired - Lifetime
-
1990
- 1990-01-31 GR GR89300125T patent/GR890300125T1/en unknown
-
1992
- 1992-06-18 GR GR920401315T patent/GR3004980T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ES2009723T3 (en) | 1993-02-16 |
| JPH01135795A (en) | 1989-05-29 |
| ATE75750T1 (en) | 1992-05-15 |
| IT8722343A0 (en) | 1987-10-20 |
| GR890300125T1 (en) | 1990-01-31 |
| GR3004980T3 (en) | 1993-04-28 |
| IT1223313B (en) | 1990-09-19 |
| EP0312867A1 (en) | 1989-04-26 |
| DE3870801D1 (en) | 1992-06-11 |
| ES2009723A4 (en) | 1989-10-16 |
| DE312867T1 (en) | 1989-10-05 |
| US4921848A (en) | 1990-05-01 |
| EP0312867B1 (en) | 1992-05-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2813610B2 (en) | Bile acid derivative, method for producing the same, and pharmaceutical composition containing the same | |
| RU2712033C2 (en) | Deuterated derivative of chenodeoxycholic acid and pharmaceutical composition containing said compound | |
| JP3122448B2 (en) | Fluorinated bile acid derivatives, process for producing the same, and pharmaceutical compositions containing them | |
| WO1998027106A1 (en) | Aminosterol ester compounds | |
| CZ113494A3 (en) | Derivatives of nor-bile acids, process of their preparation and use of said compounds as medicaments | |
| JP2816589B2 (en) | Bile acid derivative, method for producing the same, and pharmaceutical composition containing them | |
| KR970002642B1 (en) | Androstane 17-carboxylic-acid esters, their preparation and medicaments containing them | |
| JP2001240573A (en) | Triterpene derivative and liver disease medical treatment agent | |
| WO1995010527A1 (en) | 3,17-dihydroxy-3,7,16 and/or 17-methyl-androst-5-ene compounds, derivatives thereof, and their use | |
| JP4896335B2 (en) | Chroman derivatives as estrogen compounds | |
| AP518A (en) | Spirostanyl glycosidal crystalline monohydrate. | |
| SE448870B (en) | PROCEDURE FOR PREPARING A CONJUGATE OF A PROSTAGLANDIN WITH A STEROID HORMON | |
| EP0573977B1 (en) | Novel estradiol derivative-chlorambucil conjugate, process for preparing the same, and pharmaceutical composition | |
| JP3490470B2 (en) | Bile oxysulfide derivatives | |
| JP3096480B2 (en) | Bile acid unsaturated derivatives, process for producing the same, and pharmaceutical compositions containing them | |
| EP0003090B1 (en) | 17 alpha-aryl or 17 alpha-heteroaryl steroids, process for their preparation, their use as medicines and pharmaceutical compositions containing them | |
| JP2834721B2 (en) | 17α-cyanomethylestradi-4,9-diene derivative, method for producing the same, and pharmaceutical containing the compound | |
| RU2099347C1 (en) | 17α-ACETOXY-3β-BUTANOYLHYDROXY-6-METHYLPREGNA-4,6-DIENE-20-ONE SHOWING GESTAGENIC ACTIVITY | |
| US4962099A (en) | Chemical synthesis | |
| JPS6363698A (en) | Bile acid derivative, salt and production thereof | |
| JP2002527448A (en) | Pregnane glucuronide | |
| WO2003087120A1 (en) | Estrone derivative and process for producing the same | |
| JPH07252294A (en) | Adrenocortical steroid derivative | |
| JPS63255296A (en) | Estradiol derivative | |
| JP2001523268A (en) | Mono and disulfate esters of pregnane-3,20-diol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| LAPS | Cancellation because of no payment of annual fees |